MICU1 and MICU2 Finely Tune the Mitochondrial Ca ²⁺ Uniporter by Exerting Opposite Effects on MCU Activity

Summary

Mitochondrial calcium accumulation was recently shown to depend on a complex composed of an inner-membrane channel (MCU and MCUb) and regulatory subunits (MICU1, MCUR1, and EMRE). A fundamental property of MCU is low activity at resting cytosolic Ca ²⁺ concentrations, preventing deleterious Ca ²⁺ cycling and organelle overload. Here we demonstrate that these properties are ensured by a regulatory heterodimer composed of two proteins with opposite effects, MICU1 and MICU2, which, both in purified lipid bilayers and in intact cells, stimulate and inhibit MCU activity, respectively. Both MICU1 and MICU2 are regulated by calcium through their EF-hand domains, thus accounting for the sigmoidal response of MCU to [Ca ²⁺] in situ and allowing tight physiological control. At low [Ca ²⁺], the dominant effect of MICU2 largely shuts down MCU activity; at higher [Ca ²⁺], the stimulatory effect of MICU1 allows the prompt response of mitochondria to Ca ²⁺ signals generated in the cytoplasm.

Graphical Abstract

Highlights

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  MICU1 and MICU2 form an obligate heterodimer

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  MICU1 enhances MCU opening

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  MICU2 acts as an MCU gatekeeper

Abstract

Mitochondrial calcium uptake is rapid in response to calcium signaling. Patron et al. demonstrate that this response is not intrinsic to the mitochondrial calcium uniporter (MCU) but rather is dependent on a disulfide-mediated dimer of MCU interactors (MICU1 and MICU2). At low [Ca ²⁺], MICU2 shuts down MCU activity, but after Ca ²⁺ stimulation, MICU2 inhibition is released and MICU1 enhances MCU opening.